Reduced glutamatergic signaling is a final common denominator of a number of disorders that reduce cognitive ability, including mild cognitive impairment, Alzheimer's disease, schizophrenia, ADHD, narcolepsy, autism, depression, schizophrenia and Parkinson's disease. These neurological and psychiatric disorders affect millions of people in this country and hundreds of millions across world populations. Many of these diseases are progressive and are currently incurable. The best hope for improving the quality of life of afflicted individuals may lie with mitigating the most debilitating symptoms, and certainly cognitive decline significantly impacts both the quality of life and the ability to contribute to the workforce. AMPA receptor modulators show promise in the treatment of diseases resulting in the loss of cognitive function. There are multiple classes of positive allosteric modulators that act through a common binding site to shape AMPA receptor deactivation and desensitization. The long-term goal of these studies is to study the mechanism of receptor deactivation and desensitization, and how drugs and proteins that modulate these processes exert their actions. The following specific objectives will utilize molecular and structural biology, patch clamp electrophysiology, fluorescence energy transfer, a new methodology of probing tertiary and quaternary protein complexes using metabolic biotinylation, and computational modeling: 1. To determine the efficacy of modulation of deactivation and desensitization of AMPA receptor mutations that intrinsically perturb deactivation and desensitization, using each of the three classes of modulator, in the absence or presence of the AMPA receptor accessory protein, stargazin. 2. To determine how modulation by stargazin is similar to or differs from modulation of deactivation and/or desensitization by these compounds. A biophysical approach to study modulation of deactivation and desensitization using drugs that have intrinsically different modes of action may better direct future efforts to design AMPA-selective, cognition-enhancing drugs. PUBLIC HEALTH RELEVANCE: Reduced glutamatergic signaling is a final common denominator of a number of disorders that reduce cognitive ability, including mild cognitive impairment, Alzheimer's disease, schizophrenia, ADHD, narcolepsy, autism, depression, schizophrenia and Parkinson's disease. AMPA receptor modulators show promise in the treatment of diseases resulting in the loss of cognitive function. A biophysical approach to study modulation of deactivation and desensitization using drugs that have intrinsically different modes of action may better direct future efforts to design AMPA-selective, cognition-enhancing drugs.